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Novel Progestin Signaling Molecules in the Brain: Distribution, Regulation and Molecular Mechanism of Action

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Novel Progestin Signaling Molecules in the Brain: Distribution, Regulation and Molecular Mechanism of Action University of Massachusetts Amherst ScholarWorks@UMass Amherst Open Access Dissertations 5-13-2011 Novel Progestin Signaling Molecules in the Brain: Distribution, Regulation and Molecular Mechanism of Action Karlie A. Intlekofer University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/open_access_dissertations Part of the Molecular and Cellular Neuroscience Commons Recommended Citation Intlekofer, Karlie A., "Novel Progestin Signaling Molecules in the Brain: Distribution, Regulation and Molecular Mechanism of Action" (2011). Open Access Dissertations. 366. https://scholarworks.umass.edu/open_access_dissertations/366 This Open Access Dissertation is brought to you for free and open access by ScholarWorks@UMass Amherst. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. NOVEL PROGESTIN SIGNALING MOLECULES IN THE BRAIN: DISTRIBUTION, REGULATION AND MOLECULAR MECHANISM OF ACTION A Dissertation Presented by KARLIE A. INTLEKOFER Submitted to the Graduate School of the University of Massachusetts Amherst in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2011 Neuroscience and Behavior Program © Copyright by Karlie A. Intlekofer 2011 All Rights Reserved NOVEL PROGESTIN SIGNALING MOLECULES IN THE BRAIN: DISTRIBUTION, REGULATION AND MOLECULAR MECHANISM OF ACTION A Dissertation Presented by KARLIE A. INTLEKOFER Approved as to style and content by: _____________________________________ Sandra L. Petersen, Chair ______________________________________ John J. Peluso, Member ______________________________________ Pablo E. Visconti, Member _______________________________________ Rolf O. Karlstrom, Member __________________________________________ Jerry Meyer, Department Head Neuroscience and Behavior Program DEDICATION To Mom, Dad, Dan, Adrien, Jay and my closest friends, for their love and support ACKNOWLEDGMENTS I would like to thank Dr. Sandy Petersen, who has served as a supportive mentor and guided me through the doctorate and publishing process. Sandy has provided invaluable insight into my work while allowing me to explore many different techniques and approaches. Her ability to provide a challenging and creative work environment have allowed me to grow as a researcher and as an individual. I would like to thank my labmates, past and present, in the Petersen lab: Eser Yilmaz, Sudha Krishnan, Leah Aggison, Evelyn Santos, Sarah Fadden, Jinyan Cao, Lan Ji, Michael Cunningham, and Drs. Maristela Poletini, Paula Moura, Javier Del Pino and Kay Son. I give special thanks to Ted Hudgens, who taught me important techniques and shared ideas and advice. I am also very thankful for Michael Cunningham, Paula Moura, Leah Aggison and Emily Merchasin for their unwaning friendship and support. I am very grateful to Dr. Thomas Zoeller and members of his laboratory. In particular, Dave Sharlin, Judy Brewer, Ruby Bansal and Stephanie Giera have provided helpful insights that have aided in producing this work. I also want to recognize fellow NSB graduate students Bryan Olson, Carrie Mahoney, Patrick Taylor and Thalia Gilbert for helpful insight and support, as well as thought-provoking discussions and laughter. I am thankful to Drs. John J. Peluso, Pablo Visconti and Rolf Karlstrom for their generous gift of time and expertise as committee members. I thank the Neuroscience and Behavior Program for providing a diverse research environment and their help and support in completing this work. Finally, I thank SAPAI and all associated staff for their support in organizing and writing this document. v ABSTRACT NOVEL PROGESTIN SIGNALING MOLECULES IN THE BRAIN: DISTRIBUTION, REGULATION AND MOLECULAR MECHANISM OF ACTION MAY 2011 KARLIE A. INTLEKOFER, BS. COLORADO STATE UNIVERSITY Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor Sandra L. Petersen Progesterone regulates female reproduction in many ways, yet it is still unclear how signals are conveyed through nuclear and extranuclear receptors. The traditional notion was that progesterone binds classical progesterone receptors to alter gene transcription. This view has been challenged by the discovery of additional progesterone signaling molecules important for progesterone actions in non-neural cells. In granulosa cells, the progesterone receptor membrane component 1 (Pgrmc1) mediates progesterone effects by forming a receptor complex with binding partner, Serpine mRNA binding protein 1, but it is unknown whether these molecules function similarly in the brain. To begin to address these issues, I investigated the neural role of Pgrmc1 in female mouse brain, rat brain and in neural cells. By examining the neuroanatomical localization, hormonal regulation, and colocalization of Pgrmc1 within key neurons in the neural control of ovulation, Pgrmc1 emerged as a candidate signaling molecule likely to mediate progesterone functions. Furthermore, Pgrmc1 levels regulate the expression of several diverse genes and signaling pathways in neural cells. Taken together, these results demonstrate that Pgrmc1 function is likely to impact diverse neural functions. vi TABLE OF CONTENTS Page ABSTRACT .................................................................................................................... vi LIST OF TABLES ......................................................................................................... xiv LIST OF FIGURES ........................................................................................................ xv CHAPTER 1. PROGESTIN MECHANISM OF ACTION IN THE CNS ......................................... 1 1.1 Introduction ..................................................................................................... 1 1.2 Sources and Synthesis ..................................................................................... 1 1.2.1 Progesterone Biosynthetic Pathway ................................................. 2 1.3 Effects of P 4 in the Central Nervous System .................................................. 4 1.3.1 Neuroprotection ............................................................................... 4 1.3.2 Reproductive Functions ................................................................... 5 1.4 The Classical Progesterone Receptor (Pgr) .................................................... 7 1.5 Progesterone Receptor Membrane Component-1 (Pgrmc1) ........................... 9 1.6 References ..................................................................................................... 13 2. DISTRIBUTION OF MRNAS ENCODING CLASSICAL PROGESTIN RECEPTOR, PROGESTERONE MEMBRANE COMPONENTS 1 AND 2, SERPINE MRNA BINDING PROTEIN 1, AND PROGESTIN AND ADIPOQ RECEPTOR FAMILY MEMBERS 7 AND 8 IN RAT FOREBRAIN ............................................... 24 2.1 Abstract ......................................................................................................... 24 2.2 Introduction ................................................................................................... 25 2.3 Materials and Methods .................................................................................. 27 2.3.1 Animals and Tissue Preparation .................................................... 27 2.3.2 Probe Preparation ........................................................................... 28 vii 2.3.3 ISHH .............................................................................................. 28 2.3.4 Validation of probe specificity....................................................... 29 2.3.5 Data Analysis ................................................................................. 30 2.4 Results ........................................................................................................... 31 2.4.1 Probe Specificity ............................................................................ 31 2.4.2 Distribution of Pgrmc1, Serbp1, Pgrmc2, Paqr7, Paqr8 and Pgr mRNAs ....................................................................................... 31 2.4.3 Diencephalon ................................................................................. 31 2.4.4 Telencephalon ................................................................................ 32 2.5 Discussion ..................................................................................................... 33 2.6 List of Tables ................................................................................................ 40 2.6.1 Sequences for Oligodeoxynucleotidyl Probes Used in ISHH Studies ............................................................................................... 40 2.6.2 Oligodeoxynucleotidyl Sequences for ISHH Validation Studies ............................................................................................... 41 2.6.3 Localization and Abundance of mRNA encoding Pgr, Pgrmc1, Serbp1, Pgrmc2, Paqr7 and Paqr8 in Female Rat Forebrain 1 .......................................................................................... 41 2.7 List of Figures 2.7.1 Photomicrographs of ISHH............................................................ 43 2.7.2 Photomicrographs of ISHH............................................................ 44 2.7.3 Photomicrographs of ISHH............................................................ 45 2.8 References ....................................................................................................
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